Epigenetic alterations are involved in the pathogenesis of many diseases. Histone deacetylases (HDACs) are epigenetic regulators that are frequently overexpressed in tumor cells and cause dysregulation of cell growth and differentiation. Histone deacetylase inhibitors (HDACi) are therefore considered as promising agents for tumor therapy and characterized extensively clinically and on a molecular level. HDACi inhibit the deacetylation of histones and many other proteins (Buchwald et al., 2009; Spange et al., 2009). As a result, HDACi modulate chromatin structure and gene expression. This further includes reexpression of tumor suppressor genes which effect differentiation, inhibition of cell growth and apoptosis. At the moment, HDACi of different drug classes are in development or in preclinical and clinical trials for cancer therapy (Quintas-Cardama et al., 2011; Pietschmann et al., 2012; Schneider et al., 2010).
HDACs can be grouped in four classes (I-IV) (Spange et al., 2009; Brandl et al., 2009), whereby class I, II and IV are defined by a zinc depending mechanism. Class II HDACs can be subdivided in IIa (HDAC4, -5, -7, -9) and IIb (HDAC6, -10). Class III HDACs need NAD+ as a cofactor. Whilst HDACs of class I and IV are expressed ubiquitously, they are primarily localized in the nucleus. In contrast, class II HDACs can move from the nucleus to the cytoplasm and show higher tissue specifity (Spange et al., 2009; Brandl et al., 2009).
So-called pan-HDACi have a wide range of cytotoxic profile due to the inhibition of several HDAC isoforms. In contrast, isoenzyme-selective HDAC inhibitors appear to be more suitable considering the therapy and to have fewer side effects. They usually do not generate the undesired side effects which are associated with the broad inhibition of HDACs (“off-target” effects) (Pandey et al., 2007).
Several HDACi are currently in clinical trials and the HDACi SAHA and depsipeptide have been FDA approved for the treatment of cutaneous T-cell lymphomas (Müller & Krämer 2010). Nevertheless, HDACi show its full activity against cancer only in combination with other cytostatic compounds (see e.g. Spange et al., 2009).
Along with the generally increasing importance of enzymes as therapy targets, HDAC6 is closely associated with the development of cancer. Whilst the expression of HDAC6 is induced by oncogenic RAS transformation and it is necessary for an efficient tumor formation. For example, HDAC6 is highly overexpressed in acute myeloid leukemia cells (AML) compared to normal cells (Lee et al., 2008).
Beneficial therapeutic effects on tumor cells have been described not only for pan-HDACi, but also for HDAC6 selective inhibitors. For example, ST80 (see FIG. 1A, compound 2) is an HDAC6 selective inhibitor with an IC50 value of circa 1 μM for HDAC6 and 31 times more selective against HDAC6 than against HDAC1 (Scott et al., 2008), which has the same antiproliferative effect in low micro molar range in myeloid cell lines and primary AML blasts as pan-HDACi. Thus, HDAC6 is a potential target structure of antileukemic therapy regimens.
Further, the influence of HDAC6 on the HSP-90 activity can also be important for the treatment efficiency (Chou et al., 2012). Amongst other things, HSP90 serves the folding and stabilization of oncogenic kinases, including the leukemia fusion protein BCR-ABL, mutated FLT3 (FLT3-ITD), c-KIT, AKT and c-RAF. HSP90 is also important for the stability of the pan-leukemic marker protein WT1 and for the leukemic fusion protein AML1-ETO (see e.g. Choudhary et al., 2009). New and highly selective HDAC6 activity modulating compounds are necessary, in order to capture the detailed molecular mechanisms.
Tubastatin A (see FIG. 1A, compound 3) and its derivatives are currently the most selective HDAC6 inhibitors. The development of this compound is based on rational structure-based design. A further increase in selectivity is possible by derivatization of the residue R. Correspondingly, the introduction of α, β-unsaturated or aromatic substituents results in a higher specificity and activity (Kalin et al., 2012).
There is a need in the art for improved HDAC inhibitors.